Deciphering the functional mechanism of zinc ions of PARP1 binding with single strand breaks and double strand breaks

Sun, Shihui; Wang, Xin; Lin, Rong-Feng; Wang, Kai

doi:10.1039/d2ra02683j

Cited by 3 publications

(4 citation statements)

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“…Upon detecting DNA damage, PARP-1 binds to the SSBs in DNA and directly participates in the BER pathway . PARP-1 recognizes DNA damage through the ZF domains and binds DNA at the site of the break, which changes the conformation of the helical domain (HD) and relieves autoinhibition, thereby activating the catalytic domain of PARP-1. − The activated PARP-1 catalyzes the degradation of NAD + into nicotinamide and ADP-ribose, and subsequently uses ADP-ribose as a substrate for synthesizing PAR . As a consequence, a substantial amount of negative charge is imparted to poly ADP-ribosylated histones as well as PARP-1, which leads to their dissociation from the negatively charged DNA strands due to repelling; this, in turn, relaxes the chromosomes and promotes the recruitment of other DNA-repair enzymes such as XRCC1, LIG3, and POLB at the site of DNA damage. , In addition, PARP-1 may also bind to specific PARP-binding motifs in the recruited proteins in a noncovalent manner to promote DNA-damage repair (Figure ).…”

Section: Parp-1-mediated Dna-repair Pathwaymentioning

confidence: 99%

Advances in Development of Selective Antitumor Inhibitors That Target PARP-1

Liu,

Chen,

et al. 2023

J. Med. Chem.

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Section: Parp-1-mediated Dna-repair Pathwaymentioning

confidence: 99%

Advances in Development of Selective Antitumor Inhibitors That Target PARP-1

Liu,

Chen,

et al. 2023

J. Med. Chem.

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“…Previous studies have clarified the functional mechanism of the DBD binding to damaged DNA [10,11,[14][15][16]38,39]. The main function of ZnF1 and ZnF2 is to identify and stabilize DNA structures, which provides a structural basis for the further repair of damaged DNA.…”

Section: Conformational Changes In Znf1mentioning

confidence: 99%

“…MD simulation has been broadly employed to unveil the detailed interaction mechanisms between drugs and target proteins [ 14 , 21 , 22 ]. Inhibitors related to the CAT domain of PARP1 have been widely studied through experiments and computational methods [ 2 , 12 , 19 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…The main function of the N-terminal DNA-binding domain (DBD) is to recognize and repair damaged DNA structures under certain conditions. The recognition and repair mechanisms of the DBD have been preliminarily elucidated, including the functional mechanism of zinc ions in the whole recognition process [14][15][16]. The BRCT (breast cancer susceptibility gene (BRCA) C-terminus) domain can mediate the DNA transfer of PARP1 [9,13].…”

Section: Introductionmentioning

confidence: 99%

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How ligands regulate the binding of PARP1 with DNA: Deciphering the mechanism at the molecular level

Wang

Lai

et al. 2023

PLoS ONE

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The catalytic (CAT) domain is a key region of poly (ADP-ribose) polymerase 1 (PARP1), which has crucial interactions with inhibitors, DNA, and other domains of PARP1. To facilitate the development of potential inhibitors of PARP1, it is of great significance to clarify the differences in structural dynamics and key residues between CAT/inhibitors and DNA/PARP1/inhibitors through structure-based computational design. In this paper, conformational changes in PAPR1 and differences in key residue interactions induced by inhibitors were revealed at the molecular level by comparative molecular dynamics (MD) simulations and energy decomposition. On one hand, PARP1 inhibitors indirectly change some residues of the CAT domain which interact with DNA and other domains. Furthermore, the interaction between ligands and catalytic binding sites can be transferred to the DNA recognition domain of PARP1 by a strong negative correlation movement among multi-domains of PARP1. On the other hand, it is not reliable to use the binding energy of CAT/ligand as a measure of ligand activity, because it may in some cases differs greatly from the that of PARP1/DNA/ligand. For PARP1/DNA/ligand, the stronger the binding stability between the ligand and PARP1, the stronger the binding stability between PARP1 and DNA. The findings of this work can guide further novel inhibitor design and the structural modification of PARP1 through structure-based computational design.

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Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

Mousavi,

Rimaz,

Zeynizadeh

2024

ACS Chem. Neurosci.

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Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)one (1), aryl(or heteroaryl)glyoxal monohydrates (2a−h), and hydrazine monohydrate (NH 2 NH 2 •H 2 O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a−h). After synthesis and characterization of the mentioned cinnolines (3a−h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including

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Deciphering the functional mechanism of zinc ions of PARP1 binding with single strand breaks and double strand breaks

Abstract: Poly(ADP-ribose)polymerase 1 (PARP1) is a key target for treatment of cancer-related diseases. Detailed structural changes DBD in PARP1 during the binding process with DNA were investigated and the dynamic conformational differences of DBD caused by zinc ions were revealed.

Cited by 3 publications

References 46 publications

Advances in Development of Selective Antitumor Inhibitors That Target PARP-1

Advances in Development of Selective Antitumor Inhibitors That Target PARP-1

How ligands regulate the binding of PARP1 with DNA: Deciphering the mechanism at the molecular level

Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

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